Clinical manifestations of heart failure include shortness of breath, fatigue, and fluid retention (pulmonary congestion and peripheral edema). Patients suffering from heart failure need daily monitoring of the body weight to detect fluid retention so that adjustments to lifestyle and restrictions on sodium and fluid intake can be implemented as early as possible. Reducing sodium intake helps to reduce blood volume, water and sodium in the body, and to reduce blood pressure, which relieves the symptoms of heart failure.
Chronic heart failure is a heart dysfunction that is mainly due to pump dysfunction caused by the progressive decline in ventricular myocyte contractility. In the course of chronic heart failure, myocardial calcium homeostasis is damaged, manifested as decreases in the rise of intracellular calcium transient and its slower decay. This change is considered to be the main cause for impairment of myocardial contractility. Therefore, increasing calcium intake may alleviate blood pressure and sodium retention while maintaining normal myocardial contractility. In addition, the calcium ion is essential for a variety of physiological activities in the body, e.g., the biological potential on both sides of the cell membrane, normal nerve conductivity, and normal muscle contraction and relaxation.
LCZ696 (Entresto) is an angiotensin receptor neprilysin inhibitors (ARNi) that was developed by Novartis, which received FDA approval in July 2015. It treats chronic heart failure patients having reduced ejection fractions and can reduce death and hospitalization due to heart failure. LCZ696 is a complex containing anionic forms of sacubitril (AHU-377) and valsartan at a 1:1 ratio, sodium cations, as well as water molecules. Chinese Patent No. CN 200680001733.0 covers the complex and its crystalline forms.
LCZ696 is highly hygroscopic. It is found that, after ten days under high humidity conditions, LCZ696 absorbs water and turns into a liquid form. It is well known that hygroscopicity causes difficulties in granulations, disintegration, dissolution of the solid form during the formulation process, affecting the stability and efficacy of the drug product. Hygroscopic compounds also require more expensive and complex excipients, manufacturing processes, and storage facilities. Therefore, it is desirable to obtain a compound that is low in hygroscopy, more stable, and overall more effective.